Submissions for variant NM_001001557.4(GDF6):c.1244C>T (p.Thr415Ile)

dbSNP: rs1269055850

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001871943	SCV002276900	uncertain significance	Klippel-Feil syndrome 1, autosomal dominant; Isolated microphthalmia 4; Microphthalmia, isolated, with coloboma 6; Leber congenital amaurosis 17	2023-06-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 415 of the GDF6 protein (p.Thr415Ile). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GDF6 protein function. ClinVar contains an entry for this variant (Variation ID: 1050339). This variant has not been reported in the literature in individuals affected with GDF6-related conditions. This variant is present in population databases (no rsID available, gnomAD no frequency).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357639	SCV001553164	uncertain significance	not provided		no assertion criteria provided	clinical testing	The GDF6 p.Thr415Ile variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs1269055850) and in control databases in 1 of 250888 chromosomes at a frequency of 0.000003986 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the Other population in 1 of 6120 chromosomes (freq: 0.000163), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), or South Asian populations. The p.Thr415 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.